FIV is a lentivirus that causes an AIDS-like disease in the domestic cat with many parallels to HIV/AIDS. As such, the system offers the smallest natural animal model for development of interventions and intervention strategies to combat and prevent lentivirus infections. The proposed studies will further define the molecular structure and replication properties of FIV with particular emphasis on defining targets for development of broad-based antivirals efficacious against both FIV and HIV. The proposed aims will continue ongoing studies to characterize receptor mechanisms shared with HIV and in addition, will utilize FIV-infected cat sera to assess the humoral antibody response to infection as a function of disease outcome. Aim 1 is directed at defining molecular interactions between the FIV envelope protein (SU) and the binding and entry receptors, CD134 and CXCR4, resp. Site-directed mutagenesis coupled with SU/receptor binding analyses by FACS and virus infectivity assays will be used to defined residues of SU critical for ligand/receptor interactions. [Sera from Progressor and Non-progressor cats will be analyzed against an overlapping peptide library to map epitopes recognized by infected cats as a function of disease progression]. Aim 2 will investigate the mechanism by which receptors are down-regulated on the infected cell by virus-encode OrfA and the consequences of down-regulation for both virus and host. Aim 3 will further investigate the role of novel anti-receptor antibodies from FIV-infected cats that block virus infection and are associated with improved health status of infected animals. Comparisons will be made between anti-receptor and anti-SU antibody titers for anti-viral activity in a large bank of naturally- and experimentally infected cats. Measurements of relative affinity and neutralization titers will be assessed as a function of health status of the infected cats. [In conjunction with Dr. VandeWoude at Colorado State University, we will create SU/receptor complexes and attempt to generate virus-blocking anti-receptor antibodies as found in Non-progressor FIV-infected cats. Such antibody responses may provide novel targets for vaccine development that may be applied to treatment/prevention of HIV infections in humans.] PUBLIC HEALTH RELEVANCE: Feline immunodeficiency virus (FIV) causes AIDS in the domestic cat with many similarities to AIDS in humans. Although structurally diverse, FIV is spread by blood contact and infects and kills CD4+ T cells and other targets common with HIV infection in humans. In addition, the two lentiviruses share common enzymatic functions and receptor interactions that make FIV a natural animal model for development of broad-based intervention strategies directly applicable to treating HIV infections in man.